Is there a future for selective estrogen-receptor modulators in osteoporosis?

One of the trickiest exercises in science is to predict the future. Any prediction about selective estrogen-receptor modulators (SERMs) is, therefore, questionable. Having said this, the logical answer to this question is ‘Yes, why not?’

The relationship between osteoporosis development and menopause is clear. Estrogen deprivation induces a series of involutional changes in several organs and tissues. Women experience menopausal effects in the skin, the cardiovascular system, lipoproteins, the uro-genital tract, etc. and, indeed, in bone with an accelerated bone loss [Raisz, 2005]. However, the most disturbing issue for a large proportion of women in menopause is the climacteric symptoms, mainly hot flashes. The discovery of SERMs, systemic molecules capable of exerting a tissue-specific effect [Cosman and Lindsay, 1999; Riggs and Hartmann, 2003], sometimes activating, sometimes inactivating the response in a hormone receptor, was a fascinating, even revolutionary, development.

In osteoporosis, SERM therapy began with the unexpected finding of the protective effects of tamoxifen against bone loss [Love et al. 1992; Powles et al. 1996], although this was detrimental for premenopausal women. The specificity of the molecule for breast cancer indications [Early Breast Cancer Trialists’ Collaborative Group, 2005] and a series of side effects [Fisher et al. 1994] restricted the drug’s use for the treatment of osteoporosis. However, almost immediately a strong new candidate appeared: raloxifene. Initially developed for breast cancer indications, it was rapidly redirected towards the prevention and treatment of osteoporosis. The compound held great promise. Increase in bone mineral density, important although not dramatic, was associated with a reduction in vertebral fractures [Delmas et al. 1997; Ettinger et al. 1999]. In addition, a striking decrease (76%) in breast cancer incidence, in particular in estrogen receptor-positive tumors [Cummings et al. 1999], with no effect on the endometrium, added huge value to the drug. Moreover, positive effects on lipid profile offered the potential to reduce the risk of cardiovascular diseases [Johnston et al. 2000]. Raloxifene was also associated with a reduction in total low-density lipoprotein concentration with no increase in triglycerides. However, patients often reported hot flashes, leg cramps, swelling, flu-like symptoms, joint pain and sweating. The drug also increased the incidence of deep venous thrombosis/pulmonary embolism, as does hormone replacement therapy (HRT), and severe stroke. In summary, raloxifene was a good alternative to HRT, safer for the breast and endometrium but at the cost of not alleviating (rather worsening) the climacteric syndrome.

At this point, the results of the Women’s Health Initiative [Rossouw et al. 2002] study generated a true earthquake in the management of menopausal women. Before that, hormone therapy was theoretically protective for the heart, good for bone and capable of reducing vertebral and nonvertebral fractures and perfectly controlled the climacteric syndrome. On the assumption that replacing a missing hormone (an approach similar to diabetes or hypothyroidism therapies) was the ‘true’ solution, obstetricians/gynecologists, general practitioners and other specialists began prescribing HRT to almost every postmenopausal woman who showed up in their offices. Not least important, women experienced improvement in their sexual life and skin rejuvenation. What else could we ask for? We had found the drug of eternal youth! Unfortunately, however, the horizon was not so clear. Endometrium, breast and cardiovascular problems [Black et al. 1996; Manson et al. 2003; Rossouw et al. 2002; Wassertheil-Smoller et al. 2003] successively hammered the drug, raising an enormous concern for patients and prescribers. In the case of breast cancer, women on hormone therapy suffered an excess incidence of 42 cases of breast cancer per approximately 8000 treatments compared with the placebo group, or 0.5% of patients treated with HRT. All of these adverse effects made the use of hormone therapy plummet.

Therefore, this was a perfect time for SERMs to appear on the scene! A new ‘Fierabras balsam’ (a fabulous remedy described by Cervantes in Don Quixote as able to completely cure all diseases) was available that would provide long, healthy, youthful and happy life for women. Why do we not have over-the-counter, prescription-free SERMS available today to be plucked from the shelves of supermarkets and drug stores? What went wrong?

The first problem was with bone. Only vertebral fractures were reduced, with no reduction in hip or nonvertebral fractures [Ettinger et al. 1999]. Other molecules showed fracture reductions in a critical fracture location, the hip [Black et al. 1996; Harris et al. 1999; McClung et al. 2001]. For years, physicians had it in their heads that hip fractures were the most severe consequence of osteoporosis because of their mortality, morbidity and heavy economic burden [Bentler et al. 2009; Kannus et al. 1996; Wolinsky et al. 1997]. Therefore, raloxifene was perceived as a ‘weaker’ antiosteoporosis compound than the other drugs. Successive demonstrations of the severe consequences of vertebral fractures [Black et al. 1999; Greendale et al. 2000] did not change this misconception. However, with HRT regimens in clear decline for women in the first decade or two after menopause, when vertebral fractures are the problem and hip fracture incidence is extremely low, there was room for raloxifene in the treatment of osteoporosis, with the added value of protective effects against breast cancer.

Nevertheless, the level of use of raloxifene did not come close to the previous rates of HRT use. What was the cause? For obstetricians/gynecologists and for postmenopausal women seeking medical care, climacteric syndrome was the main therapeutic target. Explain to a woman with severe hot flashes that a drug will help her in future years, can avoid vertebral fractures, not harm her uterus and even benefit breast health, in exchange for the burden of a lack of relief, or even worsening, of a syndrome severely interfering with her everyday quality of life. The likely response is fairly obvious. Furthermore, SERMS were still understood to be estrogen-like compounds, which caused reluctance to accept them, given all the negative information widely expressed in the media about hormone therapy.

The solution for SERMs to succeed in the market, especially given that the appearance of aromatase inhibitors stole momentum from their breast cancer indications, was an improved therapeutic profile. In osteoporosis, this means fracture reduction in nonvertebral bones and, even more, in the hip. Three excellent candidates were in the running, in parallel, at this time to achieve that objective: arzoxifene, lasofoxifene and bazedoxifene. Unfortunately, arzoxifene was not able to show superior results over raloxifene [Cummings et al. 2011] and its commercialization was aborted. Lasofoxifene received an initial US Food and Drug Administration nonapproval in 2005 due to a lack of large studies, although it was later approved by the European Medicines Agency in 2008. However, despite better fracture protection than raloxifene [Cummings et al. 2010], lasofoxifene was not commercialized because of a company decision. Only bazedoxifene survived the end of phase III trials and is available for prescription, in spite of an antifracture efficacy quite similar to raloxifene [Silverman et al. 2008].

What do the two SERMS available for the prevention and treatment of osteoporosis, raloxifene and bazedoxifene, offer? Without a doubt, women in their fifties and sixties benefit from reduction of the risk of vertebral fractures, which are associated with severe deterioration in quality of life, chronic morbidity and reduced life expectancy. These drugs also reduce the risk of estrogen-receptor-positive breast cancer and improve the efficiency of systematic screening with mammograms because they reduce the radiographic density of the gland. In addition, SERMs have a beneficial impact on lipid profile and favorably alter biochemical markers of cardiovascular risk, although they do not reduce the coronary events rate [Barrett-Connor et al. 2006]. Moreover, a positive effect on bone quality [Byrjalsen et al. 2008] and the lack of association with problems like osteonecrosis of the jaw (no cases described) or atypical femoral fractures further reinforce their safety. However, we must always pay attention to their contraindication in cases of risk of venous thrombosis or pulmonary embolism.

What do these compounds lack? Again, they have no effect on the chief complaint in the early postmenopausal period. They do not control the climacteric syndrome. A strategy of combining low doses of estrogen with bazedoxifene [Lindsay et al. 2009; Lobo et al. 2009] is currently promoted in an attempt to pick the better of the two molecules and achieve bone efficacy, no breast or endometrium harm and a decrease in hot flashes. The initial results show a good effect along these lines but longer follow-up observations will have the last word on the efficacy and safety of this strategy.

Therefore, we still wait for the perfect SERM. What would be the ideal profile for an unbeatable drug for the postmenopausal woman? This real ‘Balsam of Fierabras’ for these patients will offer reduced risk of bone fracture at all the skeletal locations, including the hip; neutral effects on the endometrium and at least the same benefit for breast health as available drugs; full control of climacteric symptoms; relief of vaginal dryness and dyspareunia; and total safety in terms of cardiovascular problems, mainly coronary, cerebrovascular and even venous thrombosis propensity. Other potential benefits, such as prevention of tooth loss or protection of the pelvic floor, would also be welcomed.

Active research is currently underway in the field of the hormone-receptor modulators. For glucocorticoid and androgen receptors, there would be great therapeutic value in ligands that are able to activate the ‘good’ effects, being able to neutralize or, even better, shut down the negative actions of the natural hormones. However, in terms of epidemiology, menopause remains the problem with the greatest impact that needs to be solved. We can hope that in the future, new SERMs with an almost ideal profile may yet become available.

In summary, what can be said about the available SERMs and their value today? In the first two decades after menopause, in those women at high risk of osteoporotic fracture, SERMs are still a first-line therapeutic option, although women should be warned about the possibility of worsening menopausal symptoms. Balancing the benefits with the potential side effects, SERMs offer suitable bone protection at this age and do not jeopardize the use of other antiosteoporosis drugs later in life if osteoporosis is still an evolving problem. The effect of SERMs on bone tissue is ‘physiological’ and no long-term skeletal issues are anticipated. SERMs can increase hot flashes, and therefore should be prescribed cautiously immediately following menopause. Therefore, their present value needs to be revisited because of their benefits for younger postmenopausal women. Their future, if research succeeds in improving their profile, could even be brilliant.